N omega-nitro-L-arginine methyl ester inhibits inflammatory liver injury induced by interleukin-2.
Administration of interleukin-2 (IL-2) for treatment of metastatic disease often results in inflammatory liver injury. Previous studies have implicated increased leukocyte and platelet adhesion and enhanced nitric oxide production as causative factors in the development of IL-2-induced hepatic injury. This study investigated the capacity of N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthesis inhibitor, to limit IL-2-induced hepatic edema and hepatocellular damage in mice. Using hepatic intravital microscopy, we also examined the effects of L-NAME on IL-2-induced increases in leukocyte and platelet adhesion. Administration of IL-2 increased leukocyte and platelet adhesion in post-sinusoidal venules and decreased hepatic perfusion. Cotreatment with L-NAME had no effect on leukocyte adhesion but increased platelet-endothelial adhesion and microvascular thrombosis. Chronic IL-2 treatment induced hepatic edema and hepatocellular injury. However, coadministration of L-NAME attenuated IL-2-induced edema and completely inhibited hepatocellular damage. These findings suggest that nitric oxide may play a central role in IL-2-induced inflammatory liver injury.
Lentsch
A B
AB
The Center for Applied Microcirculatory Research, Department of Physiology and Biophysics, University of Louisville, Kentucky, USA. ablent@umich.edu
Edwards
M J
MJ
Sims
D E
DE
Miller
F N
FN
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D004487:Edema / Q000139:chemically induced; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors*; D008099:Liver / Q000098:blood supply; D008107:Liver Diseases / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010973:Platelet Adhesiveness / Q000187:drug effects; D010976:Platelet Count / Q000187:drug effects; D013927:Thrombosis / Q000139:chemically induced
D004791:Enzyme Inhibitors; D007376:Interleukin-2; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D019331:NG-Nitroarginine Methyl Ester